G Model BONSOI-4154; No. of Pages 3
ARTICLE IN PRESS Joint Bone Spine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Editorial
Ehlers–Danlos syndrome in rheumatology: Diagnostic and therapeutic challenges
a r t i c l e
i n f o
Keywords: Hypermobility Recurrent dislocation Ehlers–Danlos syndrome Collagen Genetic diseases Orphan diseases
1. Introduction Ehlers–Danlos syndrome (EDS) is a vastly heterogeneous group of hereditary connective-tissue diseases characterized by abnormalities of the skin and joints. The seminal description by Ehlers and Danlos applies only to a fraction of all EDS cases [1,2]. Transmission is usually autosomal dominant but may be autosomal recessive or, in a small minority of cases, X-linked. EDS of any type is rare, with a prevalence generally estimated at about 1/5000 [3]. The classification of EDS is complex and changing. The revised Villefranche classification was a major first stride toward discriminating among the various types of EDS and describing their clinical features [4], thereby allowing the identification of genetic abnormalities in fairly uniform patient subgroups. This classification has changed over time (Table 1) [5], and a meeting has been held in Ghent in 2015 to introduce further refinements. Mutations in one or more genes have been identified for most of the reported EDS presentations [6]. The affected genes usually encode collagen chains, although a few encode enzymes involved in connective-tissue metabolism. In the most common type of EDS known as the hypermobility type (80% of all cases of EDS according to several studies), the disease-causing gene remains unidentified, except in the tiny minority of cases transmitted on an autosomal recessive basis and related to tenascin-X gene mutations. Some measures of joint hypermobility can occur in all types of EDS. However, one can distinguish between vascular-type EDS, a severely life-threatening condition with a prevalence of only about 1/100,000, and several even less common types listed in Table 1, on the one hand; and types characterized selectively by osteoarticular manifestations, on the other. These predominantly osteoarticular forms are types I, II, and III in the conventional classification, which are the classical and hypermobility types in the newer classification. These osteoarticular forms are the least rare among EDS types. They raise three challenges: entertaining the diagnosis,
confirming then disclosing the diagnosis and, finally, providing treatment despite the current lack of standardization in this area. 2. Clues to Ehlers–Danlos syndrome in rheumatology outpatients Patients with EDS may be seen during childhood, either because of a family case or because of clinical manifestations. In other instances, the diagnosis is not considered until adulthood. The presentation includes cutaneous and articular manifestations, and some patients may have a vast array of other symptoms [7]. Patients with classical EDS (i.e., types I and II; prevalence 1/20,000 to 1/50,000) present with abnormalities of the skin and joints. The skin is abnormally extensible, fragile, and velvety to the touch. Skin wounds heal slowly, leaving cigarette paper-like scars, and bruising occurs easily. The joint abnormalities include hypermobility, whose criteria are listed in Table 2, arthralgia, and a history of dislocation or subluxation episodes. There is a continuum not only for the symptoms, but also for the outcomes, and types I and II differ only regarding the severity of the manifestations. Support for the diagnosis of EDS can be obtained from biochemical and electronic microscopy testing of tissue samples. Genetic testing has been reported to identify a disease-causing mutation in 50% to 90% of cases, thereby confirming the diagnosis. Hypermobility EDS, which is by far the most common type, with a prevalence of 1/10,000, shares many similarities with classical EDS. Multiple and recurrent sprains and dislocations are usually the most prominent manifestations. The main difference with classical type EDS is that no tissue, molecular, or genetic marker has been identified to date, despite ongoing research efforts. The diagnosis consequently rests on clinical arguments. The main diagnostic challenge is distinguishing hypermobility EDS from other conditions. One differential diagnosis is benign joint hypermobility syndrome (BJHS, also known as hyperlaxity syndrome), which is extremely common in the general population and frequently runs in families. Hypermobility EDS is usually considered to carry a better prognosis than classical EDS, although some patients seem to experience severe manifestations or complications such as recurrent dislocations, deep arthralgia, disability, and even social isolation. Recent studies showed that a non-negligeable proportion of patients with hypermobility EDS also had dysautonomia or functional symptoms such as headaches, cramps, dystonia, myalgia, constipation, dysuria, dyspareunia, and fatigue or exercise intolerance [8,9]. A very commonly reported symptom is orthostatic intolerance
http://dx.doi.org/10.1016/j.jbspin.2015.04.002 1297-319X/© 2015 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie.
Please cite this article in press as: Challal S, et al. Ehlers–Danlos syndrome in rheumatology: Diagnostic and therapeutic challenges. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.04.002
G Model
ARTICLE IN PRESS
BONSOI-4154; No. of Pages 3
Editorial / Joint Bone Spine xxx (2015) xxx–xxx
2 Table 1 Classification of Ehlers–Danlos syndrome. Type number
Transmission
Genes
Clinical type
Clinical presentation
I Gravis
AD
COL5A1
Classical
Joint hypermobility, skin hyperextensibility, impaired wound healing, bruising
II Mitis III
AD AD
Hypermobility
Joint hypermobility, minor skin abnormalities (smooth skin)
IV
AD
COL5A2 ? Very rarely TNXB COL3A1
Vascular
VI
AR
PLOD1
Kyphoscoliosis
VIIA
AD
COL1A1
Arthrochalasia
Thin translucent skin; marked bruising; high risk of arterial, intestinal, or uterine rupture; hypermobility of the small joints Kyphoscoliosis, joint hypermobility, scleral fragility, risk of arterial rupture Severe joint hypermobility, bilateral developmental dysplasia of the hip
VIIB
AD
COL1A2
VIIC
AR
ADAMTS2
Multiplex congenita Dermatosparaxis
Other V VIII
X-linked
?
AD
Heterogeneous? One locus at 12p13
X
AR
Progeroid
AR
Periodontal
Severe skin fragility, sagging skin, joint hypermobility, blue sclerae Extremely rare Periodontal inflammation with loss of teeth, joint hypermobility, velvety skin with pretibial plaques Extremely rare Fibronectin deficiency Loss of skin elasticity, joint hypermobility, atrophic scars, hypotonia, progeria
AD: autosomal dominant; AR: autosomal recessive.
responsible for anxiety and malaise [10]. These symptoms, which may be at the forefront of the clinical picture, are also seen in patients with fibromyalgia and can constitute major challenges to the differential diagnosis. Thus, a patient with BJHS and fibromyalgia may be given a mistaken diagnosis of EDS. The absence of a reliable diagnostic test for hypermobile EDS is an added source of difficulty. An unproven but reasonable hypothesis is that these functional symptoms are related to abnormalities in the structure of collagen, which is a ubiquitous protein. Some authors take the position that hypermobility EDS is not a rare genetic disease. They believe that EDS can be diagnosed based chiefly on the functional manifestations, without reference to the widely recognized criteria for this syndrome. This position survives because no definitive biological or genetic test is available for hypermobility EDS [5]. It may result in the diagnosis of hypermobility EDS in 2% of all individuals with disabilities, many of whom actually have fibromyalgia, sometimes combined with hypochondriasis [11]. Current data on familial genetic diseases do not support this position, which should be viewed with circumspection given the current gaps in knowledge about EDS. Some patients with multiple-site pain, fatigue, and a number of functional manifestations may feel disappointed if they learn they do not have EDS, i.e., a well-defined diagnosis that opens access to management in referral centers for genetic or rare diseases and, in France, confers a right to full reimbursement of all disease-related healthcare costs by the statutory health insurance system. Furthermore, some of these patients may need to receive various components of the care provided to patients with a definitive diagnosis of EDS, such as prevention of recurrent dislocations. The wisest approach may consist in sharing the diagnostic uncertainty with the patient, perhaps in some cases giving a diagnosis of joint hypermobility combined with a range of functional manifestations, rather than applying the EDS label in the absence of diagnostic proof or availability of definitive markers. In the future, advances in genetic testing will no doubt lead to changes in this strategy.
The differential diagnoses of EDS include not only BJHS, which may be familial, but also a number of inherited collagen disorders, as well as other connective-tissue diseases. Diagnostic challenges are greatest in the pediatric population, as the clinical manifestations are easier to recognize in adulthood, although some signs (such as joint hypermobility) may become less marked or resolve over time. Inherited collagen diseases that may mimic EDS include moderate forms of osteogenesis imperfecta (due to COL1A1 and COL1A2 mutations), Stickler syndrome (possible mutation in 6 different collagen genes), and Ullrich-type muscle dystrophies (mutations in collagen 6 genes). Among connective-tissue diseases, the main differential diagnoses are Marfan syndrome and related conditions (e.g., Loeys–Dietz disease). Finally, joint hyperlaxity is among the manifestations of several genetic diseases (e.g., Williams syndrome and FMR1 premutations), skin hyperextensibility (cutis laxa, elastic pseudoxanthoma, De Barsy syndrome), or both (e.g., occipital horn syndrome due to ATP7A gene mutations and filaminopathies with periventricular heterotopia due to FLNA gene mutations). 3. Management of Ehlers–Danlos syndrome types I, II, and III Only symptomatic treatments are available for EDS. In types I, II, III, they consist of multiple measures: • psychological support should be provided as soon as the diagnosis is disclosed, not only to the patient, but also to the family members. Patients should be informed about the type of EDS they have and reassured that severe vascular manifestations are exceedingly rare in classical and hypermobility EDS; • therapeutic patient education plays a major role in the management of EDS; • joint abnormalities should be comprehensively evaluated and unwanted joint events prevented. Thus, patients should be
Please cite this article in press as: Challal S, et al. Ehlers–Danlos syndrome in rheumatology: Diagnostic and therapeutic challenges. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.04.002
G Model
ARTICLE IN PRESS
BONSOI-4154; No. of Pages 3
Editorial / Joint Bone Spine xxx (2015) xxx–xxx Table 2 Beighton’s criteria: a score ≥ 5 indicates joint hypermobility. Joint
Finding
Points
Passive forced extension of the little finger > 90◦
Not possible
0
Unilateral Bilateral Not possible
1 2 0
Unilateral Bilateral Not possible
1 2 0
Unilateral Bilateral Not possible
1 2 0
Unilateral Bilateral Not possible
1 2 0
Possible
1
Forced passive flexion of the thumb until it touches the forearm
Forced elbow hyperextension > 10◦
Forced knee hyperextension > 10◦
Bending forward and placing the hands flat on the floor without bending the knees
•
• •
•
•
3
Finally, the treatment phase requires a multidisciplinary approach, either at a specialized center (of which few exist) or via a network orchestrated by the rheumatologist and primary-care physician. Disclosure of interest
advised to take care while performing certain movements and to avoid movements likely to induce joint dislocation, both at work and during other activities. Custom-fit compression hosiery to protect the skin and joints is under evaluation. Orthotic devices and physical therapy may be in order; patients should be helped to cope with anxiety, fatigue, and chronic pain. They should receive dietary advice and an evaluation of their work ability; the chronic fatigue, fatigability, and sleep disturbances should be given appropriate attention; the systemic symptoms identified by history-taking and physical examination require evaluation and treatment; examples include dysuria and constipation; no specific medications are available. Analgesics are often required and may be given orally or via a patch. Intra-articular injections of glucocorticoids or local anesthetics, aimed solely at symptom relief, may prove helpful. Some patients may benefit from follow-up at a pain clinic. Patients may request a number of non-validated treatments, whose lack of efficacy and potential for adverse effects should be discussed; finally, the primary-care physician and other healthcare providers should be informed, since EDS is an extremely rare disease. Patients may be told how to contact self-help organizations.
The management strategy can be divided into three phases. The diagnostic phase should ideally include genetic counseling and testing, which can be performed at a referral center; furthermore, careful attention should be paid to the differential diagnosis. The second phase is treatment initiation, which requires selecting the measures needed based on the patient’s symptoms and establishing a close collaboration among the osteoarticular diseases specialist and a network of other healthcare professionals and social workers.
The authors declare that they have no conflicts of interest concerning this article. References [1] Danlos M. Un cas de cutis laxa avec tumeurs par contusion chronique des coudes et des genoux (xanthome juvénile pseudo-diabétique de MM Hallopeau et Macé de Lépinay). Bull Soc Fr Dermatol Syphiligr 1908;19:70–2. [2] Ehlers E. Cutis Laxa, Neigung zu Haemorrhagien in der Haut, Lockerung Mehrerer Artikulationen. Derm Zschr 1901;18:173–5. [3] Castori M, Camerota F, Celletti C, et al. Natural history and manifestations of the hypermobility type Ehlers–Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A 2010;152A:556–64. [4] Beighton P, De Paepe A, Steinmann B, et al. Ehlers–Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers–Danlos National Foundation (USA) and Ehlers–Danlos Support Group (UK). Am J Med Genet 1998;77:31–7. [5] Byers PH, Murray ML. Ehlers–Danlos syndrome: a showcase of conditions that lead to understanding matrix biology. Matrix Biol 2014;33:10–5. [6] Malfait F, de Paepe A. Reference module in biomedical sciences, 2013, from Brenner’s encyclopedia of genetics, 2, 2nd ed; 2013, http://dx.doi.org/ 10.1016/B978-0-12-374984-0.00465-4. [7] de Paepe A, Malfait F. The Ehlers–Danlos syndrome, a disorder with many faces. Clin Genet 2012;32:1–11. [8] De Wandele I, Rombaut L, Malfait F, et al. Clinical heterogeneity in patients with the hypermobility type of Ehlers–Danlos syndrome. Res Dev Disabil 2013;34:873–81. [9] De Wandel PT, Calders P, Peersman W, et al. Autonomic symptom burden in the hypermobility type of Ehlers–Danlos syndrome: a comparative study with two other EDS types, fibromyalgia,and healthy controls. Semin Arthritis Rheum 2014;44:353–61. [10] Rowe PC, Barron DF, Calkins H, et al. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers–Danlos syndrome. J Pediatr 1999;135:494–9. [11] Trabelsi N, Hamonet C. Contribution à l’épidémiologie du syndrome d’Ehlers–Danlos syndrome. J Readapt Med 2012;32:51–5.
Salima Challal a,b,c Emeline Minichiello a,b,c Benoit Funalot d,e,f Marie-Christophe Boissier a,∗,b,c a Service de rhumatologie, hôpital Avicenne, CHU Avicenne-Jean Verdier-René Muret, AP–HP, 125, rue de Stalingrad, 93009 Bobigny, France b Université Paris 13, 93000 Bobigny, France c Inserm UMR 1125, 93000 Bobigny, France d Département de génétique, AP–HP, GH Henri-Mondor, 94000 Créteil, France e Université Paris-Est-Créteil, 94000 Créteil, France f Inserm UMR 955, 94000 Créteil, France ∗ Corresponding
author. E-mail address: [email protected] (M.-C. Boissier) Accepted 10 March 2015 Available online xxx
Please cite this article in press as: Challal S, et al. Ehlers–Danlos syndrome in rheumatology: Diagnostic and therapeutic challenges. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.04.002
ARTICLE IN PRESS Joint Bone Spine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Editorial
Ehlers–Danlos syndrome in rheumatology: Diagnostic and therapeutic challenges
a r t i c l e
i n f o
Keywords: Hypermobility Recurrent dislocation Ehlers–Danlos syndrome Collagen Genetic diseases Orphan diseases
1. Introduction Ehlers–Danlos syndrome (EDS) is a vastly heterogeneous group of hereditary connective-tissue diseases characterized by abnormalities of the skin and joints. The seminal description by Ehlers and Danlos applies only to a fraction of all EDS cases [1,2]. Transmission is usually autosomal dominant but may be autosomal recessive or, in a small minority of cases, X-linked. EDS of any type is rare, with a prevalence generally estimated at about 1/5000 [3]. The classification of EDS is complex and changing. The revised Villefranche classification was a major first stride toward discriminating among the various types of EDS and describing their clinical features [4], thereby allowing the identification of genetic abnormalities in fairly uniform patient subgroups. This classification has changed over time (Table 1) [5], and a meeting has been held in Ghent in 2015 to introduce further refinements. Mutations in one or more genes have been identified for most of the reported EDS presentations [6]. The affected genes usually encode collagen chains, although a few encode enzymes involved in connective-tissue metabolism. In the most common type of EDS known as the hypermobility type (80% of all cases of EDS according to several studies), the disease-causing gene remains unidentified, except in the tiny minority of cases transmitted on an autosomal recessive basis and related to tenascin-X gene mutations. Some measures of joint hypermobility can occur in all types of EDS. However, one can distinguish between vascular-type EDS, a severely life-threatening condition with a prevalence of only about 1/100,000, and several even less common types listed in Table 1, on the one hand; and types characterized selectively by osteoarticular manifestations, on the other. These predominantly osteoarticular forms are types I, II, and III in the conventional classification, which are the classical and hypermobility types in the newer classification. These osteoarticular forms are the least rare among EDS types. They raise three challenges: entertaining the diagnosis,
confirming then disclosing the diagnosis and, finally, providing treatment despite the current lack of standardization in this area. 2. Clues to Ehlers–Danlos syndrome in rheumatology outpatients Patients with EDS may be seen during childhood, either because of a family case or because of clinical manifestations. In other instances, the diagnosis is not considered until adulthood. The presentation includes cutaneous and articular manifestations, and some patients may have a vast array of other symptoms [7]. Patients with classical EDS (i.e., types I and II; prevalence 1/20,000 to 1/50,000) present with abnormalities of the skin and joints. The skin is abnormally extensible, fragile, and velvety to the touch. Skin wounds heal slowly, leaving cigarette paper-like scars, and bruising occurs easily. The joint abnormalities include hypermobility, whose criteria are listed in Table 2, arthralgia, and a history of dislocation or subluxation episodes. There is a continuum not only for the symptoms, but also for the outcomes, and types I and II differ only regarding the severity of the manifestations. Support for the diagnosis of EDS can be obtained from biochemical and electronic microscopy testing of tissue samples. Genetic testing has been reported to identify a disease-causing mutation in 50% to 90% of cases, thereby confirming the diagnosis. Hypermobility EDS, which is by far the most common type, with a prevalence of 1/10,000, shares many similarities with classical EDS. Multiple and recurrent sprains and dislocations are usually the most prominent manifestations. The main difference with classical type EDS is that no tissue, molecular, or genetic marker has been identified to date, despite ongoing research efforts. The diagnosis consequently rests on clinical arguments. The main diagnostic challenge is distinguishing hypermobility EDS from other conditions. One differential diagnosis is benign joint hypermobility syndrome (BJHS, also known as hyperlaxity syndrome), which is extremely common in the general population and frequently runs in families. Hypermobility EDS is usually considered to carry a better prognosis than classical EDS, although some patients seem to experience severe manifestations or complications such as recurrent dislocations, deep arthralgia, disability, and even social isolation. Recent studies showed that a non-negligeable proportion of patients with hypermobility EDS also had dysautonomia or functional symptoms such as headaches, cramps, dystonia, myalgia, constipation, dysuria, dyspareunia, and fatigue or exercise intolerance [8,9]. A very commonly reported symptom is orthostatic intolerance
http://dx.doi.org/10.1016/j.jbspin.2015.04.002 1297-319X/© 2015 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie.
Please cite this article in press as: Challal S, et al. Ehlers–Danlos syndrome in rheumatology: Diagnostic and therapeutic challenges. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.04.002
G Model
ARTICLE IN PRESS
BONSOI-4154; No. of Pages 3
Editorial / Joint Bone Spine xxx (2015) xxx–xxx
2 Table 1 Classification of Ehlers–Danlos syndrome. Type number
Transmission
Genes
Clinical type
Clinical presentation
I Gravis
AD
COL5A1
Classical
Joint hypermobility, skin hyperextensibility, impaired wound healing, bruising
II Mitis III
AD AD
Hypermobility
Joint hypermobility, minor skin abnormalities (smooth skin)
IV
AD
COL5A2 ? Very rarely TNXB COL3A1
Vascular
VI
AR
PLOD1
Kyphoscoliosis
VIIA
AD
COL1A1
Arthrochalasia
Thin translucent skin; marked bruising; high risk of arterial, intestinal, or uterine rupture; hypermobility of the small joints Kyphoscoliosis, joint hypermobility, scleral fragility, risk of arterial rupture Severe joint hypermobility, bilateral developmental dysplasia of the hip
VIIB
AD
COL1A2
VIIC
AR
ADAMTS2
Multiplex congenita Dermatosparaxis
Other V VIII
X-linked
?
AD
Heterogeneous? One locus at 12p13
X
AR
Progeroid
AR
Periodontal
Severe skin fragility, sagging skin, joint hypermobility, blue sclerae Extremely rare Periodontal inflammation with loss of teeth, joint hypermobility, velvety skin with pretibial plaques Extremely rare Fibronectin deficiency Loss of skin elasticity, joint hypermobility, atrophic scars, hypotonia, progeria
AD: autosomal dominant; AR: autosomal recessive.
responsible for anxiety and malaise [10]. These symptoms, which may be at the forefront of the clinical picture, are also seen in patients with fibromyalgia and can constitute major challenges to the differential diagnosis. Thus, a patient with BJHS and fibromyalgia may be given a mistaken diagnosis of EDS. The absence of a reliable diagnostic test for hypermobile EDS is an added source of difficulty. An unproven but reasonable hypothesis is that these functional symptoms are related to abnormalities in the structure of collagen, which is a ubiquitous protein. Some authors take the position that hypermobility EDS is not a rare genetic disease. They believe that EDS can be diagnosed based chiefly on the functional manifestations, without reference to the widely recognized criteria for this syndrome. This position survives because no definitive biological or genetic test is available for hypermobility EDS [5]. It may result in the diagnosis of hypermobility EDS in 2% of all individuals with disabilities, many of whom actually have fibromyalgia, sometimes combined with hypochondriasis [11]. Current data on familial genetic diseases do not support this position, which should be viewed with circumspection given the current gaps in knowledge about EDS. Some patients with multiple-site pain, fatigue, and a number of functional manifestations may feel disappointed if they learn they do not have EDS, i.e., a well-defined diagnosis that opens access to management in referral centers for genetic or rare diseases and, in France, confers a right to full reimbursement of all disease-related healthcare costs by the statutory health insurance system. Furthermore, some of these patients may need to receive various components of the care provided to patients with a definitive diagnosis of EDS, such as prevention of recurrent dislocations. The wisest approach may consist in sharing the diagnostic uncertainty with the patient, perhaps in some cases giving a diagnosis of joint hypermobility combined with a range of functional manifestations, rather than applying the EDS label in the absence of diagnostic proof or availability of definitive markers. In the future, advances in genetic testing will no doubt lead to changes in this strategy.
The differential diagnoses of EDS include not only BJHS, which may be familial, but also a number of inherited collagen disorders, as well as other connective-tissue diseases. Diagnostic challenges are greatest in the pediatric population, as the clinical manifestations are easier to recognize in adulthood, although some signs (such as joint hypermobility) may become less marked or resolve over time. Inherited collagen diseases that may mimic EDS include moderate forms of osteogenesis imperfecta (due to COL1A1 and COL1A2 mutations), Stickler syndrome (possible mutation in 6 different collagen genes), and Ullrich-type muscle dystrophies (mutations in collagen 6 genes). Among connective-tissue diseases, the main differential diagnoses are Marfan syndrome and related conditions (e.g., Loeys–Dietz disease). Finally, joint hyperlaxity is among the manifestations of several genetic diseases (e.g., Williams syndrome and FMR1 premutations), skin hyperextensibility (cutis laxa, elastic pseudoxanthoma, De Barsy syndrome), or both (e.g., occipital horn syndrome due to ATP7A gene mutations and filaminopathies with periventricular heterotopia due to FLNA gene mutations). 3. Management of Ehlers–Danlos syndrome types I, II, and III Only symptomatic treatments are available for EDS. In types I, II, III, they consist of multiple measures: • psychological support should be provided as soon as the diagnosis is disclosed, not only to the patient, but also to the family members. Patients should be informed about the type of EDS they have and reassured that severe vascular manifestations are exceedingly rare in classical and hypermobility EDS; • therapeutic patient education plays a major role in the management of EDS; • joint abnormalities should be comprehensively evaluated and unwanted joint events prevented. Thus, patients should be
Please cite this article in press as: Challal S, et al. Ehlers–Danlos syndrome in rheumatology: Diagnostic and therapeutic challenges. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.04.002
G Model
ARTICLE IN PRESS
BONSOI-4154; No. of Pages 3
Editorial / Joint Bone Spine xxx (2015) xxx–xxx Table 2 Beighton’s criteria: a score ≥ 5 indicates joint hypermobility. Joint
Finding
Points
Passive forced extension of the little finger > 90◦
Not possible
0
Unilateral Bilateral Not possible
1 2 0
Unilateral Bilateral Not possible
1 2 0
Unilateral Bilateral Not possible
1 2 0
Unilateral Bilateral Not possible
1 2 0
Possible
1
Forced passive flexion of the thumb until it touches the forearm
Forced elbow hyperextension > 10◦
Forced knee hyperextension > 10◦
Bending forward and placing the hands flat on the floor without bending the knees
•
• •
•
•
3
Finally, the treatment phase requires a multidisciplinary approach, either at a specialized center (of which few exist) or via a network orchestrated by the rheumatologist and primary-care physician. Disclosure of interest
advised to take care while performing certain movements and to avoid movements likely to induce joint dislocation, both at work and during other activities. Custom-fit compression hosiery to protect the skin and joints is under evaluation. Orthotic devices and physical therapy may be in order; patients should be helped to cope with anxiety, fatigue, and chronic pain. They should receive dietary advice and an evaluation of their work ability; the chronic fatigue, fatigability, and sleep disturbances should be given appropriate attention; the systemic symptoms identified by history-taking and physical examination require evaluation and treatment; examples include dysuria and constipation; no specific medications are available. Analgesics are often required and may be given orally or via a patch. Intra-articular injections of glucocorticoids or local anesthetics, aimed solely at symptom relief, may prove helpful. Some patients may benefit from follow-up at a pain clinic. Patients may request a number of non-validated treatments, whose lack of efficacy and potential for adverse effects should be discussed; finally, the primary-care physician and other healthcare providers should be informed, since EDS is an extremely rare disease. Patients may be told how to contact self-help organizations.
The management strategy can be divided into three phases. The diagnostic phase should ideally include genetic counseling and testing, which can be performed at a referral center; furthermore, careful attention should be paid to the differential diagnosis. The second phase is treatment initiation, which requires selecting the measures needed based on the patient’s symptoms and establishing a close collaboration among the osteoarticular diseases specialist and a network of other healthcare professionals and social workers.
The authors declare that they have no conflicts of interest concerning this article. References [1] Danlos M. Un cas de cutis laxa avec tumeurs par contusion chronique des coudes et des genoux (xanthome juvénile pseudo-diabétique de MM Hallopeau et Macé de Lépinay). Bull Soc Fr Dermatol Syphiligr 1908;19:70–2. [2] Ehlers E. Cutis Laxa, Neigung zu Haemorrhagien in der Haut, Lockerung Mehrerer Artikulationen. Derm Zschr 1901;18:173–5. [3] Castori M, Camerota F, Celletti C, et al. Natural history and manifestations of the hypermobility type Ehlers–Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A 2010;152A:556–64. [4] Beighton P, De Paepe A, Steinmann B, et al. Ehlers–Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers–Danlos National Foundation (USA) and Ehlers–Danlos Support Group (UK). Am J Med Genet 1998;77:31–7. [5] Byers PH, Murray ML. Ehlers–Danlos syndrome: a showcase of conditions that lead to understanding matrix biology. Matrix Biol 2014;33:10–5. [6] Malfait F, de Paepe A. Reference module in biomedical sciences, 2013, from Brenner’s encyclopedia of genetics, 2, 2nd ed; 2013, http://dx.doi.org/ 10.1016/B978-0-12-374984-0.00465-4. [7] de Paepe A, Malfait F. The Ehlers–Danlos syndrome, a disorder with many faces. Clin Genet 2012;32:1–11. [8] De Wandele I, Rombaut L, Malfait F, et al. Clinical heterogeneity in patients with the hypermobility type of Ehlers–Danlos syndrome. Res Dev Disabil 2013;34:873–81. [9] De Wandel PT, Calders P, Peersman W, et al. Autonomic symptom burden in the hypermobility type of Ehlers–Danlos syndrome: a comparative study with two other EDS types, fibromyalgia,and healthy controls. Semin Arthritis Rheum 2014;44:353–61. [10] Rowe PC, Barron DF, Calkins H, et al. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers–Danlos syndrome. J Pediatr 1999;135:494–9. [11] Trabelsi N, Hamonet C. Contribution à l’épidémiologie du syndrome d’Ehlers–Danlos syndrome. J Readapt Med 2012;32:51–5.
Salima Challal a,b,c Emeline Minichiello a,b,c Benoit Funalot d,e,f Marie-Christophe Boissier a,∗,b,c a Service de rhumatologie, hôpital Avicenne, CHU Avicenne-Jean Verdier-René Muret, AP–HP, 125, rue de Stalingrad, 93009 Bobigny, France b Université Paris 13, 93000 Bobigny, France c Inserm UMR 1125, 93000 Bobigny, France d Département de génétique, AP–HP, GH Henri-Mondor, 94000 Créteil, France e Université Paris-Est-Créteil, 94000 Créteil, France f Inserm UMR 955, 94000 Créteil, France ∗ Corresponding
author. E-mail address: [email protected] (M.-C. Boissier) Accepted 10 March 2015 Available online xxx
Please cite this article in press as: Challal S, et al. Ehlers–Danlos syndrome in rheumatology: Diagnostic and therapeutic challenges. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.04.002
